The search for molecule(s) responsible for the formation, proliferation, differentiation and maintenance of tissues and organs, such as haematopoietic, gut, neuronal, brain and muscle tissues, has been extensive as there is a tremendous need for factors useful for treating conditions involving degradation or damage to these tissues, as well as various disorders associated with defects in these processes. The present invention relates to a family of proteins designated as Frazzled, which family shares homology to the ligand binding domain of the Frizzled proteins family.
The structures of several proteins encoded by a gene family designated as frizzled, have previously been elucidated. Frizzled protein family members have been shown to bind to the Wingless (Wg) protein, the Drosophila prototype of the Wnt family. Bhanot et al., Nature, 382:225-230 (1996). In mammals and other species, the Frizzled family of proteins are membrane bound receptor molecules which bind proteins produced by the family of wnt genes. Wang et al., J. Biol. Chem., 271:4468-4476 (1996). Wnt genes play multiple roles in cell proliferation and differentiation and are expressed in a variety of adult and embryonic tissues and organs, for example, brain, lung, pancreas, liver, spleen, kidney, intestines and/or other tissues and organs.
Several Frizzled-related genes (frzbs) have been identified which encode proteins resembling Frizzleds, i.e., receptors lacking most of the transmembrane domain(s). It has been postulated that Frzbs function as soluble antagonists of Wnt signals. Hoang, et al., JBC 271:26131 (1996), identified a frizzled homologue (which they named frzb) expressed primarily in the cartilaginous cores of developing long bones which was thought to be involved in morphogenesis of the mammalian skeleton. Unlike the genes encoding the Frizzled family of proteins, the frzb gene does not contain seven transmembrane domains. The bovine and human Frzb are 94% identical. Ratner, et al., PNAS 94:2859 (1997) identified in mouse eye cDNA libraries three DNA sequences encoding secreted frizzled-related proteins (sFRP-1, SFRP-2, and sFRP-3). Wang, et al., Cell 88:757 (1997), isolated a Xenopus homologue of Frzb containing an amino-terminal Frizzled motif and which was soluble and secretable. It was also found to bind and inhibit Wnt-8 (a ventral inducer) and to act as a functional inhibitor of Wnt signalling through direct extracellular binding. Leyns, et al., Cell 88:747 (1997), have identified a secreted protein, Frzb-1, also having sequence similarity to the extracellular domain of Frizzled.